BRPI0309765B1 - non-irritating and warming lubricating antifungal gel compositions - Google Patents

Abstract

This invention relates to substantially anhydrous warming, non-toxic and nonirritating lubricating compositions containing polyhydric alcohols, a gelling agent and alternatively a pH adjusting agent for treating fungal and bacterial infections. The invention also relates to methods of using such compositions for warming, lubrication, administration of active ingredients and for preventing or treating dysmenorrhea.

Description

Report of the Invention Patent for "NON-IRRITANT AND HEATING ANTI-FUNGAL GEL COMPOSITIONS".

FIELD OF THE INVENTION The present invention relates to essentially anhydrous clear gel compositions which are capable of dissolving certain azole antifungal compounds and releasing them in a soluble form.

Currently, in all commercially available azole-containing antifungal and antibacterial formulations, antifungal agents such as myconazole, terconazole, itraconazole, clotrimazole and other azoles exist in an unsolvable form, dispersed in cream bases, suppositories or ointments as crystals. micronized. In general, drug agents are much more effective when released in a solution form. Azole compounds have almost no solubility, if any, in classical solvents used in the solid or semi-solid dosage forms currently used to release these compounds.

BACKGROUND OF THE INVENTION Most women, at least once in their lives, experience vaginal fungal infection. There are a variety of reasons for these infections to occur. Widespread use of antibiotics stimulates Candida albicans overgrowth. This condition, known as vulvovaginitis (Vulvovaginal Candidiasis or WC) is usually treated by antifungal azole agents applied either intravaginally or orally. However, patients often mistakenly believe that their vaginal infection is a fungal infection that can be treated with over-the-counter antifungal (OTC) products. Such patients may actually have a bacterial infection rather than a fungal infection. OTC antifungal products are not effective against bacterial infections (also known as “bacterial vaginosis”), a chronic condition that is much more common than toilet. Clinically, bacterial vaginosis is a polymicrobial vaginal infection caused by an increase in the number of anaerobic organisms with a concomitant reduction of Lactobacillus in the vagina. Indiscriminate use of OTC antifungal products can lead to an increased risk of masking bacterial infections.

Under stable conditions, Lactobacillus, the predominant organism in the normal vagina, controls the growth of anaerobes and other bacteria by producing hydrogen peroxide and lactic acid from vaginal glycogen to maintain vaginal acidity. Therefore, it is of paramount importance that products and compositions intended for vaginal application for the treatment of fungal or bacterial infections do not adversely affect the Lactobacillus population and allow a healthy acidic vaginal pH to be maintained.

Although the incidence of vaginitis and bacterial vaginosis is surprising, there are only a small number of products currently available to treat bacterial infections. For example, MetroGel-Vaginal® (metronidazole) and Cleosin® (clindamycin) are available by prescription to treat bacterial vaginosis. However, it has been seen that about 15-30% of patients who get bacterial vaginosis develop a toilet infection after treatment.

Therefore, there is a pressing need for a product that will treat both WC and bacterial vaginosis by destroying the causative organisms, and thus treat vaginal infections caused by both fungi and bacteria.

Known treatments for WC and bacterial vaginosis generally refer to novel antifungal and antibacterial chemical entities and penetration enhancing formulations that increase the availability of existing compounds.

For example, WO 99 / 63968A1 refers to increasing the solubility of insufficiently soluble antifungal and antibacterial agents through aqueous preparations and reversibly thermogelifying aqueous preparations using polysorbate and / or polyoxyethylene hardened castor oil. WO99 / 43343A1 and United States Patent No. 6,093,391 describe increased activity of peptide-based agents and other treatment agents, including azole antifungals, using Pluronic Ρ85 as a gelling agent. GB 2,327,344 discusses antifungal / antibacterial azole derivatives in formulations in combination with silver salts for the treatment of wounds, ulcers and burns. GB 2,187,956 and United States Patent No. 4,803,066 describe a topical pharmaceutical composition using a mixture of a silver antimicrobial compound in combination with an azole compound to treat burns, ulcers, lesions and infections of the skin and mucous membrane. . FR 2,805,745 discloses antifungal and antiseptic nail polish compositions containing a cellulosic film-forming agent in solution with an organic solvent and formalin. WO99 / 18791 describes the application of an amino acid derivative in the form of salt or free acid, in which nitrogen atoms of two or more amino acid molecules are chained by a hydrocarbyl-substituted hydrocarbyl group as a compound. antifungal agent and / or an antibacterial compound.

Earlier efforts to solubilize antifungal azole products such as miconazole, terconazole, itraconazole, clotrimazole and others have involved the use of organic solvents such as ethyl alcohol in combination with other organic solvents. However, alcohol-based compositions are irritating to mucous membranes and cannot be used in preparations intended for vaginal or oral application.

Therefore, there is a need for an efficient and effective product that is capable of treating both WC and bacterial vaginosis while selectively allowing survival and maintenance of the Lactobacillus vaginal population.

An object of this invention is to provide a means for solubilizing insoluble or poorly soluble azole compounds in order to increase their effectiveness and spectrum of their activity. It is also an object of this invention to develop novel compositions that will be effective for treating both fungal and bacterial infections.

SUMMARY OF THE INVENTION

The compositions and methods of this invention relate to clear gel compositions in which azole compounds are incorporated in a completely soluble state. The compositions and methods of this invention contain polyhydric alcohols as solvents for azole derivatives, more particularly antifungal imidazole and triazole derivatives. The compositions of this invention also preferably contain a gelling agent, more preferably a gelling cellulosic derivative. Preferably, the gelling cellulosic derivatives useful in the compositions of this invention are hydrocolloids. Classic cellulose based gelling agents are only water soluble and do not form gels when used in combination with organic solvents. There are additional advantages to the use of the compositions of this invention in releasing antimicrobial agents to patients in that the compositions of this invention may have a heat effect on the tissue to which they are applied as well as to lubricate said tissue. The compositions of this invention may also be used as warm lubricant compositions which are non-toxic and non-irritating and which may be used as personal lubricants designed to come into contact with the skin or mucosa. When mixed with water, the gel and jelly compositions of this invention raise the temperature or produce heat.

This has a calming effect on the fabrics to which these compositions are applied. This substantially eliminates the cold sensation or perception that conventional personal lubricants convey in the application.

The compositions of this invention have excellent lubrication characteristics. The gel and jelly compositions of this invention are more lubricating than even the commercially available aqueous lubricants. The compositions of this invention, in particular the jelly compositions of this invention, are new in that their lubricating power increases in dilution with water. Known commercially available aqueous compositions decrease the lubricating power upon dilution with water. This is a particular advantage in that the compositions of this invention may be used in connection with the wet vaginal or oral mucosa and will become increasingly slippery upon exposure to moisture.

Although anhydrous compositions are commonly perceived as irritating to the skin and mucous membranes, the gel and jelly compositions of this invention are surprisingly non-irritating.

The compositions of this invention may be applied to the skin or mucous membranes, preferably to the vaginal or oral mucosa. The compositions of this invention are preferably essentially anhydrous and preferably contain at least one polyhydric alcohol.

It has been theorized that when polyhydric alcohols contained in the compositions of this invention come into contact with water or body moisture in humans, they react with ambient water molecules causing a rise in temperature or produce heat, thereby having an effect. soothing on the fabrics to which these compositions are applied.

Surprisingly, and contrary to the general belief that polyhydric alcohols in compositions are mucosal irritants, it has been found that the compositions of this invention containing said polyhydric alcohols are non-irritating. It has been theorized that hydrocolloids useful in the compositions and methods of this invention will swell on contact with water, producing a lubricating gel layer. This layer physically blocks the irritating action of other anhydrous elements of the compositions of this invention. In addition, as the polyhydric alcohols useful in the compositions of this invention are humectants and humectants, when hydrocolloids swell and form thin films on mucosal tissues, the films retain humectants on the tissue surface. Thus, the compositions of this invention overcome dryness conditions such as vaginal dryness and dryness of the mouth caused by various factors including menopause and aging, as well as various disease conditions.

Therefore, the compositions of this invention are very mild to skin and mucous membranes. The compositions of this invention are soothing when applied to oral mucous membranes and may function by relieving secondary irritation of the mouth and throat. The combination of polyhydric alcohols in the compositions of this invention may also be used as a vehicle for solubilizing otherwise insoluble drugs, including, but not limited to, antifungals, antibacterials, antivirals, analgesics, antiinflammatory steroids, contraceptives, local anesthetics, hormones and the like.

Preferably, the compositions of this invention are maintained at an acidic pH. An acid pH is very useful for maintaining healthy vaginal and oral flora, particularly for maintaining Lactobacilli in the vaginal area. Conventional buffers or acids are known to be insoluble in anhydrous compositions. Preferably, the compositions of this invention contain an organic acid which is soluble therein to maintain an acidic pH. Even more preferably, the organic acid is lactic acid. Lactic acid is not only soluble in the anhydrous compositions of this invention, it is a natural acid produced in human tissue and is very safe for use in the compositions of this invention. A similar organic acid is particularly useful as an acidifying agent which may assist in lowering the pH of the tissues where the compositions of this invention are applied. This will help maintain the natural acidic environment of the mucosa and stimulate the growth of appropriate flora.

The compositions of this invention may also preferably contain an insulating agent which functions by preserving the rise in temperature while maintaining heat within the composition after it has been applied to the skin or mucosa. More preferably, honey may be used as an insulating agent.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph representing the percentage of viable Epidermis cells versus Exposure Time using the composition of Example 1. Figure 2 is a graph representing the percentage of viable Epidermis cells versus Exposure Time The composition of Example 2. Figure 3 is a graph representing the percentage of viable Epidermis cells versus Exposure Time using a State of the Art Non-Irritating Product (KY Liquid®). Figure 4 is a graph representing the percentage of viable cells of the epidermis versus exposure time using a state-of-the-art (Prosensual®) product. Figure 5 is a graph comparing the Lubricating Power versus Time (in Seconds) of the composition of Example 1 and three industry leading Personal Lubricants.

DETAILED DESCRIPTION OF

PREFERRED EMBODIMENTS

The compositions of this invention are essentially anhydrous, preferably containing less than about 20% water, more preferably containing less than about 5% water, and even more preferably containing less than about 3% water.

Preferably, the compositions of this invention contain at least one polyhydric alcohol, and more preferably two polyhydric alcohols. Preferably, at least one of the polyhydric alcohols of the compositions of this invention is a polyalkylene glycol or others selected from the following group: glycerine, propylene glycol, butylene glycol, hexalene glycol or polyethylene glycol of various molecular weights and the like and / or combinations thereof. of these. More preferably, the compositions of this invention contain a polyethylene glycol; even more preferably, the polyethylene glycol may be selected from the following group: polyethylene glycol 400 or polyethylene glycol 300. The compositions of this invention should contain polyhydric alcohols in an amount of from about 80% to about 98% by weight of the polyethylene glycol. composition.

The compositions of this invention should also preferably contain one or more water soluble cellulose-derived film-forming polymers, gums, chitosans or the like. Preferably, such cellulose-derived polymers are hydroxyalkylcellulose polymers. More preferably, the hydroxyalkylcellulose polymer is selected from the following group: hydroxyethylcellulose, carboxyboxymethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose and the like. More preferably, the hydroxyalkylcellulose polymer is hydroxypropylcellulose, such as Klucel® which is commercially available from Hercules Incorporated of Wilmington, Delaware. Most cellulose-derived polymers are water soluble and insoluble in anhydrous solvents except for hydroxypropylcellulose, which is completely soluble in the anhydrous polyhydric portion of the compositions of this invention. Preferably, the compositions of this invention contain from about 0.15% to about 0.6% by weight of hydroxypropylcellulose to produce flowable gels and from about 1% to about 4% of hydroxypropylcellulose to produce thixotropic jellies.

The gel compositions of this invention even more preferably contain hydroxypropylcellulose in combination with polyhydric alcohols such as propylene glycol, polyethylene glycol 300 or 400 or glycerine to completely dissolve imidazole and triazole antifungal compounds and form clear thixotropic gels. The solubilization of these compounds not only increases their effectiveness, but also increases their activity spectrum. Surprisingly, it has been seen that these soluble antifungal compounds exert antibacterial activity in addition to their antifungal activity. Treatment agents of an insoluble state cannot readily and directly permeate fungal or bacterial cell walls, thereby limiting their availability and restricting their mode of action. Once the compounds are made soluble, they become able to permeate into the fungal and bacterial cell walls. As this increases its effectiveness against organisms, a much lower concentration or dose of compound is required to treat an infection. In addition, they cannot treat infections caused by more than one type of organism at the same time. This will make treating vaginal infections simpler and more practical, as women will be able to use a preparation to treat infections regardless of the causative organism.

Another unexpected advantage of the compositions of this invention is that the presence of lactic acid in the compositions of this invention serves to maintain a healthy acidic vaginal pH and therefore a healthy population of Lactobacillus. The compositions of this invention are surprisingly selective in that they combat unwanted fungal and bacterial cells while maintaining the appropriate vaginal flora population.

The compositions of this invention preferably also contain an insulating agent. More preferably, the insulating agent should be honey or esters of isopropyl alcohol and saturated high molecular weight fatty acids such as myristic or palmitic acid, for example isopropyl myristate and isopropyl palmitate. The insulating agent should be present in the compositions of this invention in an amount of from about 1% to about 5% by weight of the composition.

The compositions of this invention are unexpectedly self-preserving and may not require a preservative. However, a preservative may be added to provide additional assurance against microbial growth. A preservative may be selected from preservatives known to those skilled in the art, including, but not limited to, one or more of the following: methylparaben, benzoic acid, sorbic acid, gallic acid, propylparaben or the like. The preservative may be present in the compositions of this invention in an amount of from about 0.01% to about 0.75% by weight of the composition.

The compositions of this invention may also preferably contain an ester. More preferably, the ester is a fatty acid ester. Even more preferably, the ester may include, but is not limited to: isopropyl stearate, isopropyl myristate, isopropyl palmitate, isopropyl laurate and the like. Even more preferably, the ester is isopropyl myristate.

The compositions of this invention may contain one or more water soluble cellulose-derived polymers, gums, chitosans or the like. Said polymers contribute to the viscosity and bioadhesiveness of the compositions of this invention. Preferably, said cellulose derived polymers are hydroxyalkylcellulose polymers. More preferably, the hydroxyalkylcellulose polymer is hydroxypropylcellulose or Klucel®, commercially available from Hercules Incorporated, Wilmington, Delaware.

The polyhydric alcohols used in the compositions of this invention are considered theoretically useful as warm and heat producing agents. Honey acts as an insulating agent, protecting compositions from becoming too cold. The ester, preferably a fatty acid ester, functions as an emollient and lubricant. Cellulosic polymer is useful as a viscosity forming agent. The compositions of this invention are unique in that they lubricate, heat and soften the user's tissues, especially the oral and vaginal mucous membranes, without imparting a feeling of cold. In addition, they are softening and lubricating.

The compositions of this invention may be a liquid, semisolid, or solid depending upon the particular intended application thereof. The compositions of this invention may be formulated as syrupy liquid gels, flowable gel or dense jellies. Preferably, their viscosities should range from about 1,000 cps to about 7,000 cps for gels and from about 60,000 cps to about 500,000 cps for jellies. The compositions of this invention may also be formulated in soft or hard gelatin capsules, suppositories and impregnated in fabrics or polymers.

The compositions of this invention may be used as personal lubricants which impart a sensation of heat. The sensation of heat produced by the compositions of this invention is soothing to the skin or mucous membranes to which they are applied. The compositions of the invention also have a sweet and pleasant taste, which is of particular advantage when these compositions are used orally.

The compositions of this invention may also be used as personal humectants, which impart a sensation of heat when applied to the vaginal or oral mucosa. They can be used as humectants which give off a warm feeling and soothe vaginal dryness or dry mouth.

The compositions of this invention may also be used as a vehicle for releasing medication or other treatment agents to biomembranes including, but not limited to, hormones, antimicrobials, antibacterials, antibiotics, non-steroidal anti-inflammatory agents, stericides, immunodilators, anesthetics, plant extracts, vitamins, corticosteroids or antifungal agents and the like.

Antifungal agents are preferably azoles or imidoles including but not limited to, miconazole, econazole, terconazole, saperconazole, itraconazole, butaconazole, clotrimazole, thioconazole, fluconazole and ketoconazole, vericonazole, fenticonazole, posaconazole, bifonazole , oxyconazole, sulconazole, elubiol, vorconazole, isoconazole, flutrimazole, thioconazole and their pharmaceutically acceptable salts and the like. Other antifungal agents may include an allylamine or one of other chemical families, including but not limited to, ternafine, naphthyphine, amorphine, butenafine, cyclopirox, griseofulvin, undeciclenic acid, haloprogin, tolnaftate, nystatin, iodine, rilopirox, BAY 108888, purpuromycin and its pharmaceutically acceptable salts. Particularly suitable for application in the compositions of this invention are insoluble or poorly soluble azole compounds which are capable of exhibiting both antifungal and antibacterial activity upon administration in association with the methods of this invention.

Another embodiment of the invention is compositions for vulvovaginal or other mucosal application containing one or more antibiotics. The antibiotic may be selected from the group including, but not limited to, metronidazole, clindamycin, tinidazole, ornidazole, secnidazole, refaximin, trypectomycin, purpuromycin and their pharmaceutically acceptable and similar salts.

Another embodiment of the compositions of this invention includes compositions for vulvovaginal or other mucosal application containing one or more antiviral agents. Antiviral agents may preferably include, but are not limited to, immunomodulators, more preferably imiquimod, derivatives thereof, podofilox, podophylline, alpha interferon, reticules, cidofovir, nonoxynol-9 and their pharmaceutically acceptable and similar salts. .

Still other embodiments of the compositions of this invention are compositions comprising one or more spermicides. Spermicides may preferably include, but are not limited to, nonoxynol-9, octoxynol-9, dodecaethylene glycol monolaurate, Laureth 10S, and Methoxypolyoxyethylene glycol 550 Laurate and the like.

Still other embodiments of the compositions of this invention are compositions containing antimicrobial agents. Antimicrobial agents may preferably include, but are not limited to, chlorhexidine gluconate, sodium polystyrene sulfonate, sodium cellulose sulfate, micro- and submicron-sized silver particles, silver salts and other antibacterial agents known in the art. technique.

Still other embodiments of the compositions of this invention are compositions which may include local anesthetics. Local anesthetics may preferably include, but are not limited to, benzocaine, lidocaine, dibucaine, benzyl alcohol, camphor, resorcinol, menthol and diphenylhydramine hydrochloride and the like.

Compositions of the invention may also include plant extracts such as aloe vera, witch hazel, chamomile, hydrogenated soybean oil and colloidal oatmeal, vitamins such as vitamin A, D or E and corticosteroids such as hydrocortisone acetate.

Another embodiment of the compositions and methods of this invention include compositions for vulvovaginal application containing one or more hormones to treat a reduction in estrogen secretion in women needing estrogen replacement such as women with vaginal atrophy.

Hormones may preferably include, but are not limited to, estrogen selected from the group consisting of estradiol, estradiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enanthate, conjugated estrogen, estriol, estrone, estrone sulfate, ethinyl estradol, estrofurate, quinestrol and mestranol.

In another embodiment of the compositions and methods of this invention, the compositions may be useful for treating female sexual dysfunction alone as they may serve to increase blood flow to areas in which they are applied by increasing the temperature thereof. Alternatively, they may contain agents known to those skilled in the art to treat female sexual dysfunction (including different aspects of sexual dysfunction such as female sexual arousal disorder, hypoactive sexual desire disorder, orgasmic disorder and the like) as well as those for treating dyspareunia. and / or vaginismus, or vulvodynia and to relieve pain during intercourse. Such agents include hormones such as estrogen, prostaglandin, testosterone; calcium channel blockers, cholinergic modulators, alpha-adrenergic receptor antagonist, beta-adrenergic receptor agonists, camp-dependent protein kinase activators, superoxide sequestrants, potassium channel activators, estrogen-like compounds, testosterone-like compounds, benzodiazepines, adrenergic nerve inhibitors, HMG-CoA reductase inhibitors, smooth muscle relaxants, adenosine receptor modulators, and adenylyl cyclase activators. Such agents include phosphodiesterase-5 inhibitors and the like.

Another embodiment of the compositions and methods of this invention include compositions for vulvovaginal application containing one or more non-steroidal analgesic and / or anti-inflammatory agents for treating menstrual dysmenorrhea or colic. Nonsteroidal analgesic and anti-inflammatory agents may preferably include, but are not limited to, aspirin, ibuprofen, indomethacin, phenylbutazone, bromfenac, fenna, suldin, nabumetone, ketorolac, and naproxen and the like.

Still another embodiment of the compositions and methods of this invention include compositions for oral and vulvovaginal application or other mucosal application refers to a method for enhancing the absorption of active agents of the applied compositions into the mucous membrane by increasing the temperature of the mucosal membrane. composition and mucosal tissue through interaction of polyhydric alcohols in the compositions and moisture on the mucus and subsequently released heat.

Still another embodiment of the compositions of this invention includes compositions for vulvovaginal application relating to compositions and methods for preventing and / or treating dysmenorrhea by heat or intravaginal heating. Preferably, the composition heats the intravaginal area to a temperature preferably between about 37 ° C and about 42 ° C, more preferably between about 38 ° C and about 41 ° C. Compositions of the invention for application in such a method may optionally contain active agents such as analgesic and non-steroidal antiinflammatory agents for treating dysmenorrhea. The compositions of the invention may be administered directly into the vagina by means of an applicator, or may be impregnated into vaginal devices such as cotton tampons for intravaginal applications.

The compositions of this invention may be manufactured as a cotton tampon coating, or distributed throughout the absorbent cotton tampon material, or internally enclosed as a cotton tampon core. Compositions of this invention for the warm cotton buffer for preventing and / or treating dysmenorrhea preferably include a mixture of polyethylene glycols of various molecular weights produced by The Dow Chemical Company (Midland, M1) under the names CARBOWAX SENTRY PEG. 300 NF, CARBOWAX SENTRY PEG

400 NF, CARBOWAX SENTRY PEG 600 NF, CARBOWAX SENTRY PEG

900 NF, CARBOWAX SENTRY PEG 1000 NF, CARBOWAX SENTRY PEG

1450 NF, CARBOWAX SENTRY PEG 3500 NF, CARBOWAX SENTRY PEG

4000 NF, CARBOWAX SENTRY PEG 4600 NF, and CARBOWAX SENTRY PEG 8000 NF. Compositions of this invention for prophylaxis and treatment of dysmenorrhea may contain one or more water soluble cellulose-derived polymers and gums which form gels around polyhydric alcohols such as glycerine, propylene glycol and polyethylene glycols thereby reducing the dissolution of polyhydric alcohols, prolonging the release of the heat of dissolution, and regulating the elevated temperature within the range of the preferred temperature.

The compositions of this invention may be applied to the oral or vaginal mucosal tissues manually or through a vaginal swab or applicator or in any manner known to those of ordinary skill in the art.

This invention also relates to a method for determining and comparing relative amounts of irritation from particular sources using the EpiDerm® Skin Model Test as described in Example 1, such as compositions applied to skin or mucosa cells. . The following Example 1 exemplifies the application of the method of this invention.

Example 1: EpiDerm® Skin Model Test for Lubricant Irritation Testing is less toxic or less irritating whereas those with lower survival rates are more toxic. The method designated as EpiDerm® Skin Model test uses derived skin cells. human skin as target cells and is commercially available from MatTek Corporation. This test is described in Berridge, M.V., et al. (1996) The Biochemical and Cellular Basis of Cell Proliferation Assays That Use Tetrazolium Salts. Biochemistry 4: 14-19. Test materials are applied directly to the surface of the epithelial cell culture. This test has not been previously used to determine the toxicity of test materials. Toxicity of the test material is assessed based on relative tissue viability versus time. Actual Tissue Viability is determined by the reduction of MTT-dependent NAD (P) H microsomal enzymes in cultures treated with test and control articles. The negative control used in this test was deionized water and the positive control was Triton X-100. Exposed cell cultures were incubated for 4, 8, 16 and 24 hours and tested for MTT reduction. Data are shown below in Figures 1 to 4 as Relative Survival (relative MTT reduction) versus Exposure Time. Relative irritation in this test is expressed as a percentage of epidermal cell survival rate over a 24 hour period. Products with higher relative survival rates are less toxic or less irritating. The survival rate of four compositions of this invention ranged from 81.3% to 90.3%, indicating that the compositions of this invention are essentially non-irritating.

Figures 1 to 4 summarize the results of the Epidermis Skin Model Bioassay. Data are plotted as% Viable Cells versus Exposure Time ranging from 4 to 24 hours. Figures 1 and 2 represent the results for two compositions of this invention, Composition 1 and Composition 2 respectively. Figure 3 shows the results of K-Y® Liquid, a personal lubricant on the market. K-Y® Liquid is proven safe and non-irritating in animal and human experimentation and long-term human application history. Results for K-Y® Liquid showed 100.3% viable cells after 24 hours of exposure (Figure 3). Example 1 of the invention (Figure 1) and Example 2 of the invention (Figure 2) showed 91.1% and 96.9% of viable cells respectively. Figure 4 shows the results of a warm composition known in the trade. This product uses plant materials such as cinnamon, cloves, ginger and orange cloves and others for a warm feel. The results show only 37.6% of viable cells after 24 hours of exposure to this product. This indicates that such compositions will be irritating to the skin and mucous membranes. Compositions 1 and 2 of this invention, with 91.1% and 96.9% of viable cells respectively, will be virtually non-irritating. The positive control (Triton X-100) has only 22.4% viable cells within 8 hours.

Example 2: Heat Production The compositions of this invention are anhydrous and contain one or more polyhydric alcohols. When combined with water, the polyhydric alcohols used in the compositions of this invention produce a temperature increase that has a soothing effect on the fabrics to which these compositions are applied. In actual application the compositions of the invention interact with the moisture of the vaginal or oral mucosa, thereby raising the temperature or producing a sensation of heat.

The "Heat Production" data summarized in Table 1 below were generated by mixing 20 ml of each of the ingredients in Composition 1 and Composition 1 of this invention with 20 ml of water. The product temperature and water temperature were recorded before water was added to the product. After the addition of water the mixture was mixed for two minutes and the actual temperature was recorded. Glycerin, Propylene Glycol and Honey are the ingredients in Composition 1. It is clear from Table 1 that when mixed with water the temperature of the mixture increases by 5 ° C.

(9.0 ° F) for Glycerin, 7.5 ° C (13.5 ° F) for Propylene Glycol, 9.44 ° C (17.0 ° F) for Polyethylene Glycol 400 and 6.94 ° C (12.5 ° F) for the composition of Example 1 of this invention. The calculated temperature increase for Composition 1 based on temperature increase and% by weight / weight amount of each individual ingredient in the composition was 6.0415 ° C (10.875 ° F). The actual temperature increase recorded for Composition 1 was 6.94 ° C (12.5 ° F) which is 0.8985 ° C (1.625 ° F) higher than expected indicating an unexpected increase in temperature. resulting from the combination of ingredients.

HEAT PRODUCTION DATA (TEMPERATURE INCREASE IN

° F) MIXING EQUAL QUANTITY OF EACH PRODUCT WITH WATER

Calculated Temperature Increase: In order to determine the expected temperature increase of each composition, the percentage of each component in such composition was multiplied by the temperature increase produced by such component alone to obtain its expected contribution to the temperature increase. These values were added together to calculate the expected total temperature increase. These values were then compared with the actual increase in temperature produced by each composition. For example, the calculated increase in temperature produced by the composition “KY Warm®” was found in the table above as compared to the actual increase in temperature to determine the unexpectedly higher heat output of the composition: Propylene Glycol (50 % 7.5 (13.5)) = 3.75 (6.75) Glycerin (45% of 5 (9.0)) = 2.25 (4.05) Honey (5% of 0.83 ( 1.5)) = 0.0415 (0.075) Total 6.0415 (10.875) Difference: 6.94-6.0415 = 0.8985 (12.5 - 10.875 = 1.625) Example 3: Effect of Water Content on Heat Production In contact with moisture or water the heat of the solution is responsible for the heating action of the compositions of this invention. There is a concern that accidental water contamination or prolonged exposure to excessive moisture may adversely affect the heating capacity of the product. According to this example, water was added to the compositions of this invention ranging from about 1% to about 10% as outlined in Table 2 below. The contents were mixed thoroughly and the samples were allowed to stand at room temperature for 24 hours after which heat production was determined as summarized in the following paragraph. The results show that the temperature rise is proportionally reduced depending on the amount of water added but there is still a 4.86 ° C (8.5 ° F) increase in temperature to about 10% water addition. .

The results of this example are determined in Table 2 below.

Table 2: Effect of Water Content on Heat Production for K-Y

Warm®.

Example 4: Perception of Heat in Human Application A Human Application Study was conducted with 246 patients. The data produced by this study are summarized below in Table 2. Patients were asked to use the compositions of this invention. Three questions regarding heat perception during product use were asked as follows: 1. Does it heat up on contact? 2. Do you have a hot feeling? 3. Don't you feel cold?

Patients were asked to record their responses as Excellent, Very Good, Good, Fair and Bad. Positive responses are summarized in Table 2.

Table 3: HEALTH PERCEPTION IN THE HUMAN APPLICATION STUDY WITH 246 HUMAN PATIENTS USING THE COMPOSITION OF

EXAMPLE 1 OF THE INVENTION

As determined in Table 3 above, 81.64% of patients reported a positive response that the product “heats up to the touch”, 85.78% of patients felt that the product “looks hot” while 94, 53% of patients reported that the product "does not look cold".

Example 5: Lubricating Power Comparison Ahmad et al. U.S. Patent No. 6,139,848, which is hereby incorporated by reference into this report, describes a method for testing the lubricating power of various commercially known personal lubricants. In the test method described, the lubricating power of various personal lubricants marketed over a period of 300 seconds (5 minutes) was determined. The lubricating power data described in this patent indicate that the K-Y Liquid® lubricant had a higher lubricating power and had a longer duration over the 300 second test period than competitive products. Lubricating power data determined in United States Patent No. 6,139,848 had a negative (-) sign during the "stimulus" phase and a positive (+) sign during the "influence" phase of the experiment. The compositions of this invention were tested using the lubricating power test determined in U.S. Patent No. 6,129,848. However, the duration of the test was successfully extended to 16 minutes (960 seconds) and the data were processed. for “curve fitting” to eliminate the negative sign (-). The lubricating power data for composition 1 of this invention is compared to the data for KY Liquid® in Figure 5. The data indicate that composition 1 of this invention has a higher lubricating power compared to KY Liquid® and that Composition 1 maintains high lubricating power over an extended period of 16 minutes (960 seconds) and therefore lasts longer.

Example 6: Heat of the Solution It is believed that the heating effect of the compositions of this invention is caused by the heat production of the solution rather than creating the conditions for exothermic reactions. Exothermic reactions result in heat emission due to a chemical reaction between two chemicals and are uncontrollable. A similar exothermic chemical reaction may produce new chemicals or entities, some of which may not be suitable for human tissues. In contrast, when a solution is formed there is an exchange of energy due to the difference between the forces of attraction of similar and different molecules. Specifically, bonds are broken between molecules of each component being mixed and new bonds are formed between neighboring molecules of the solution or product mixture. This mechanism is different from a reaction heat because there is no chemical recombination of the constituent atoms to form products from the reactants. As can be seen from the following experiment, the maximum heat produced or the maximum temperature rise is no more than 18.8 ° F, which makes these compositions very gentle and safe. The solution process for the compositions of this invention (COMPOSITION A), for example, in vaginal fluids ("X H20") can be represented by the following physical equation: COMPOSITION A (1) + X H20 (1) COMPOSITION A ( X H20) The designation "COMPOSITION 15 (X H20)" represents that the product is a solution of 1 (mol) of COMPOSITION 15 to X (mol) of H20.

Therefore, using a COMPOSITION 15, a composition according to this invention as a personal lubricant does not alter the existing amount of naturally occurring vaginal fluids. It simply forms a solution with them. The maximum possible temperature increase from heat production by applying the compositions of this invention can be measured using thermodynamic principles. For example, Differential Scanning Calorimetry (DSC) was employed to characterize the heat released by the compositions of this invention when they come in contact with water to form a solution. In this experiment, the energy released when a thin film of a particular composition was applied to a thin film of water was measured. The results of a typical test are presented in Figure 6. The exothermic (ie negative) peak area represents the total energy released during the formation of a solution of the composition of this invention and water. Table 1 summarizes the energy released for this series of experiments.

Table 1: Summary of DSC Measurements of Heat Released by COMPOSITION 15 / Water _____________________________________________ The energy release measured by DSC is representative of the maximum energy that would be seen on the surface of the vaginal tissue. This is because the heat flux (energy flux) into the thin film of water during solution formation measured by Differential Scanning Calorimetry is equivalent to the heat flux (energy flux) that would be in the fluid on the surface of the vaginal tissue. . Therefore, thermodynamics can be used to calculate the maximum possible temperature increase as follows: where, Qmax represents the Maximum Energy Released during contact (solution formation) of Composition 15 and water; Cpm represents Thermal Capacity of Composition 15 Solution and Water; and ATmax represents Maximum Temperature Increase. Thus, by readjusting Equation 1, it was possible to calculate ATmax, the Maximum Temperature Increase, based on known or measured Maximum Released Energy values and the Thermal Capacity of the Composition Solution 15, as follows: Assuming a For normal distribution, the experimental results in Table 1 can be used to arrive at a worst-case estimate for the maximum value of Qmax as follows: Qmax = {Average Experimental Energy Release + 3 x (Standard Deviation of Energy Release Experimental)} / (Average Quantity of Composition 15) = {(340,405 mJ) + (3) (67,045 mJ)} / (22.89 mg) = (541,539 mJ / 22.89 mg) (Equation 3) (Using this as the upper limit represents 99.73% of the upper confidence limit for the normal distribution.) In the case of Cpm, the lowest of Cp for Composition 15 and Cp for Water may be used to arrive at an estimate of worst case for its minimum value. Like, Cp (Composition 15) = 0.54 cal / (g - ° C) Cp (Composition 15) = 1.00 cal / (g - ° C) so, CPm (worst case minimum) = 0.54 cal / (g - ° C) (Equation 4) Therefore, one can estimate the worst case of the maximum possible temperature increase from heat production by Composition 15 using the combination of Equations 2, 3, and 4 as follows: Thus, the maximum heat released on application of Composition 15 is at most about 10.5 ° C or 18.8 ° F, a relatively small increase in heat, indicating that increases in temperature realized by the compositions of this invention are safe and comfortable for the user.

Example 7: Heat Production Compositions 10, 11 and 12 were tested according to the following procedure to determine the extent to which said compositions produce heat in admixture with water. Data were produced by mixing 20 ml of each composition with 20 ml of water. The composition temperature and water temperature were recorded before water was added to the composition. After the water was added, the contents were mixed for two minutes and the actual temperature was recorded. The results are given in the following table: HEAT PRODUCTION DATA (TEMPERATURE INCREASE IN

° F) MIXING EQUAL AMOUNT OF EACH WATER COMPOSITION.

The increase in temperature was calculated. For Compositions 10, 11 and 12: Composition 10 Propylene Glycol (38% 7.5 (13.5)) = 2.85 (5.13) Polyethylene Glycol 400 (61.5% 9.44 (17.0)) = 5.80 (10.45) Total: 8.65 ° C (15.58 ° F) Composition 11 For Composition 11 the Calculated Temperature Increase is 8.65 ° C (15.58 ° F).

Composition 12 For Composition 12 the calculated Temperature Increase is 8.15 ° C (15.15 ° F). The Calculated Temperature for all three compositions is very close to the Actual Temperature Increase.

Example 8: Comparison of Lubricating Power Using the method for testing and comparing the lubricating power of various personal lubricants set forth in Example 3 above, the lubricating power of the compositions of this invention was determined. The following is a summary of the results: The Gel compositions of this invention are as lubricating as the aqueous gel compositions described in United States Patent No. 6,139,848 by Ahmad et al. In Figure 7, the lubricating power of commercially available KY® Jelly jelly was measured both in its commercially available form and in a 1: 1 dilution with water. In the dilution, the lubricating power did not essentially increase.

The Jelly compositions of this invention are more lubricant compared to prior art aqueous jellies known in the market. Composition 14 of this invention was measured with respect to the lubricant power as initially prepared and at a 1: 1 dilution with water. Surprisingly, its lubricating power increases substantially (about four times) in dilution. These data are represented in Figure 8. Therefore, the jelly compositions of this invention become slippery or their lubricating power is increased when these compositions are diluted with water in a 1: 1 ratio. Figure 9 demonstrates a comparison of the lubricating powers of KY® Jelly jelly and Composition 14 in their initial forms. Figure 10 illustrates the lubricating powers of two tepid gel compositions of this invention, Compositions 13 and 14, showing their high lubricating powers. Figure 11 shows KY * Ultragel and diluted Composition 14.

Example 9: Compositions of the Invention The following compositions of this invention were prepared as follows: first, propylene glycol and glycerin were mixed. A preservative and the insulating agent were then added to the mixture within the same container. The mixture was then heated to from about 35 ° C to about 45 ° C to completely dissolve the preservative. Then the mixture was cooled. Gel and jelly compositions were prepared by mixing propylene glycol, polyethylene glycol and hydroxypropylcellulose in a high speed mixer at a temperature from about 60 ° C to about 70 ° C until a gel or soft jelly was obtained. The resulting gel or jelly was cooled to a temperature between about 45 ° C and about 55 ° C and lactic acid was added. The dough was continuously mixed for about 15 minutes or until the lactic acid was dissolved. Then the mass was cooled to room temperature.

Composition 1: Propylene Glycol 50.00% Glycerin 45.00% Honey 5.00% Composition 2: Propylene Glycol 50.00% Glycerine 20.00% Isopropyl myristate 27.00% Polysorbate 60 3.00% Composition 3: Propylene Glycol 95.00% Honey 5.00% Composition 4: Propylene Glycol 50.00% Glycerin 20.00% Isopropyl myristate 29.50% Klucel HF 0.50% Composition 5: Propylene Glycol 99.50% Klucel HF 0, 50% Composition 6: Propylene Glycol 49.80% Glycerin 45.00% Honey 5.00% Preservative 0.20% Composition 7: Miconazole Nitrate 2.00% Propylene Glycol 49.80% Glycerine 43.00% Honey 5, 00% Preservative 0.20% Composition 8: Fluconazole 2.00% Propylene Glycol 49.80% Glycerin 43.00% Honey 5.00% Preservative 0.20% Composition 9: Metronidazole 3.00% Propylene Glycol 49.80% Glycerin 42.00% Honey 5.00% Preservative 0.20% Composition 10 (Gel): Propylene Glycol 38.00 Polyethylene Glycol 400 61.05 Lactic Acid 00.20 Hydroxypropylcellulose 0.75 Composition 11 (Jelly): Propylene Glycol 37 .00 Polyethylene Glycol 400 61.05 Acid Lactic 00,20 Hydroxypropylcellulose 1.75 Composition 12 (Gel): Propylene Glycol 48.00 Polyethylene Glycol 400 51.30 Lactic Acid 0.20 Hydroxypropylcellulose 0.50 Composition 13 (Frost): Propylene Glycol 48.55 Polyethylene Glycol 400 50, 00 Lactic Acid 0.20 Hydroxypropylcellulose 1.25 Composition 14 (Frost): Propylene Glycol 98.55 Lactic Acid 0.20 Hydroxypropylcellulose 1.25 Composition 15 (Frost): Polyethylene Glycol 400 98.55 Lactic Acid 0.20 Hydroxypropylcellulose 1, 25 Composition 16 (Gel): Polyethylene Glycol 400 99.50 Lactic Acid 0.20 Hydroxypropylcellulose 0.30 Composition 17 (Gel): Propylene Glycol 74.50 Glycerine 25.00 Lactic Acid 0.20 Hydroxypropylcellulose 0.30 Composition 18 (Gel ): Propylene Glycol 74.50 Polyethylene Glycol 400 25.00 Lactic Acid 0.20 Hydroxypropylcellulose 0.30 Composition 19 (Gel): Propylene Glycol 69.50 Polyethylene Glycol 400 15.00 Glycerine 15.00 Lactic Acid 2.00 Hydroxypropylcellulose 0 .30 Composition 20 (Jelly): Propile no Glycol 73.55 Polyethylene Glycol 400 25.00 Lactic Acid 0.20 Hydroxypropylcellulose 1.25 Composition 21: Propylene Glycol 47.80 Polyethylene Glycol 400 48.00 Hydroxypropylcellulose (Klucel HF) 2.00 Lactic Acid 0.20 Miconazole Nitrate 2.00 Composition 22: Propylene Glycol 35.00 Polyethylene Glycol 400 60.80 Hydroxypropylcellulose (Klucel HF) 2.00 Lactic Acid 0.20 Miconazole Nitrate 2.00 Composition 23: Propylene Glycol 48.80 Polyethylene Glycol 400 48.00 Hydroxypropylcellulose (Klucel HF) 2.00 Miconazole Nitrate 2.00 Composition 24: Propylene Glycol 47.80 Polyethylene Glycol 400 46.00 Hydroxypropylcellulose (Klucel HF) 1.00 Polyvinylpyrylidone (K29-32) 3.00 Lactic Acid 0.20 Miconazole Nitrate 2.00 Composition 25: Propylene Glycol 48.80 Polyethylene Glycol 400 48.00 Hydroxypropylcellulose (Klucel HF) 2.00 Itraconazole 2.00 Example 10: In Vitro Test for Antibacterial and Antifungal Activity Time-Destruction Studies were used In Vitro to test activity at antibacterial and antifungal agents of the compositions of this invention.

A battery of vaginal anaerobic organisms known to cause bacterial vaginal infections (BV), Candida albicans that is responsible for vulvovaginal candidiasis (WC), and lactobacillus strains were used to determine the length of contact time required to inhibit and destroy these test organisms. The results of this test are summarized in Table 3. The results show that Compositions 1, 2 and 3 of the invention kill bacteria that cause bacterial vaginal infections and Candida albicans within 0 hours or almost instantaneously.

Surprisingly the compositions of the invention had no adverse effects on lactobacilli which continued to grow even after 24 hours. These results show that the gels of this composition will be effective in treating both fungal and bacterial vaginal infections.

Claims (10)

1. Antifungal anhydrous gel compositions, characterized in that they comprise from 80 wt.% To 98 wt.% Of at least two polyhydric alcohols, a gelling agent, an imidazole antifungal and an organic acid as an adjuvant. pH. Compositions according to claim 1, characterized in that said antifungal compound is selected from the group consisting of econazole, terconazole, saperconazole, itraconazole, butaconazole, cltrimazole, thioconazole, fluconazole and ketoconazole, vericonazole, phenticonazole. sertoconazole, posaconazole, bifonazole, oxiconazole, sulconazole, elubiol, vorconazole, isoconazole, flutrimazole, thioconazole and their pharmaceutically acceptable salts. Compositions according to claim 1, characterized in that said polyhydric alcohol is selected from the group consisting of: glycerine, alkylene glycol, polyethylene glycol and a mixture thereof. Compositions according to claim 1, characterized in that said gelling agent is hydroxypropylcellulose. Compositions according to claim 1, characterized in that said organic acid is an alpha hydroxy acid. Compositions according to claim 5, characterized in that said alpha hydroxy acid is Lactic Acid. Compositions according to claim 3, characterized in that said polyethylene glycol is selected from the group consisting of: polyethylene glycol 300, polyethylene glycol 400 and a mixture thereof. Compositions according to claim 1, characterized in that said composition comprises from 75% to 99% by weight of polyhydric alcohol, from 0.1% to 1% by weight of lactic acid, and from 0 25% to 20% by weight of an antifungal agent. Compositions according to claim 1, characterized in that the composition is a clear clear gel. Compositions according to claim 1, characterized in that the composition adjusts the pH of the vagina to an acidic pH between 2 and 5.